Finding treatments for bipolar disorder is harder than for other conditions. Psychiatrist Professor Michael Berk from Deakin University explains:
‘In psychiatry we don’t understand the causes of any major disorder. We also don’t fully understand why psychiatric medicines work. The standard cure for bipolar disorder, lithium, was discovered 70 years ago. But only about 30% of people with bipolar disorder respond to lithium. We have other drugs but they have significant side effects, so adherence is problematic. A lot of people struggle with bipolar symptoms that don’t respond to treatment.’
In the past the drugs used to treat bipolar disorder were discovered by chance. Michael’s team is trying to change that. ‘What we did in this project was search in a more focussed way for drugs that could be effective,’ he says.
The team is not aiming to discover a new drug. ‘It costs more than a billion dollars to develop a new molecule into a novel chemical and take it through clinical trials. We can’t do that,’ Michael says. Instead, they are searching for drugs that could be repurposed to treat bipolar depression.
Drug discovery using brain cell lines
Michael’s team grows cell lines from his patient’s brains in the laboratory. They use the cell lines to test the effects of different drugs on bipolar disorder. When they began this process, they first had to find out what positive signals they were looking for.
‘We tickled the cells with a combination of existing drugs that we know work for bipolar disorder. Then we monitored how the drugs changed the messenger RNA signals that carry messages from DNA to tell cells to make proteins. Some signals increased and some decreased. These changes showed us some genes were being more expressed and some were being supressed. We recorded this gene expression signature in a readout.’
The team then searched for other drugs that produced a similar gene signature. ‘We screened two thousand compounds from drug libraries. We found about 20 candidates with a similar gene expression signature. Some were drugs we already use. Some were drugs with bad side effects. But we also found a few drugs that are safe, tolerable and affordable. One of these was candesartan.’
The team’s next step was to validate the effects of candesartan on animal models. They used 2 animal models for depression. ‘Depressed’ rats do not find sugary water as enjoyable or swim as long in a water tank, compared to healthy rats. So they went on to:
- test rats with sugary water to see if the drug makes them want to drink more sugary water
- test if rats swim or float when researchers put them in a water tank, to see if the drug makes them swim more.
Candesartan passed these animal model tests for depression and an animal model test for mania.
Human population studies
Other researchers had already studied the effects of candesartan on humans. Because candesartan is a high blood pressure drug, it is widely prescribed. More than 10 whole population studies compared the effects of candesartan and other high blood pressure drugs on patients. When the team analysed these studies, they found that patients taking candesartan had around half the risk of developing depression or bipolar disorder compared to patients taking other drugs for high blood pressure.
They also discovered another important piece of evidence. Clinical trials showed that when doctors treated patients with high blood pressure drugs their quality of life improved.
‘These patients were not depressed, but the improvement in their quality of life was enough for us to say this stuff does something useful to the way you feel,’ Michael says.
Together, these discoveries were strong evidence that candesartan could protect patients from depression and mania. ‘Finding that out was really cool,’ Michael recalls.
Why does drug repurposing work?
Michael says nearly 30% of drugs approved for new treatments each year are repurposed drugs. That means drugs used to treat one condition can also treat another condition. Michael explains how this works:
‘The way I think of it, the body is like a set of Lego bricks. There’s a limited number of Lego bricks but how we put them together determines what they build. In the body, molecular pathways are like Lego bricks. The same pathways operate in different organs and tissues.
‘For this reason, many medications that treat one illness also have off-target effects that might have beneficial applications in other illnesses.’
A double-blind clinical trial of candesartan for bipolar depression
The final step in the team’s research is to test candesartan in people with bipolar disorder to see if the drug improves their depression and quality of life. In this trial, 240 adult participants with moderate to severe bipolar depressive disorder will receive extra medication of either:
- a daily dose of candesartan
- or a placebo (a pill that does not contain medication).
In order not to affect the results, the participants, their carers and doctors, the clinical trial doctors and the biostatistician who will analyse the results do not know who receives candesartan and who receives a placebo.
If the trial shows candesartan helps reduce bipolar depression, Michael says the results will be easy to implement.
‘The barriers to translation are very low because candesartan is already on the market. Candesartan has a better side effect profile than almost any other psychotropic drug. It is generic and it is cheap,’ he says.
Improving people’s lives
Michael hopes this candesartan research will help improve patients’ lives.
‘Bipolar disorder is a problem that you can fix. If you treat people properly you can return them to a normal, productive life,’ he says.
‘I want to be able to exit the planet having made a difference, having done something for somebody. This job allows me that opportunity.’
The candesartan clinical trial is supported by $2.4 million from the MRFF.